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| ID | Type | Description | Link |
|---|---|---|---|
| U10HD021364 | U.S. NIH Grant/Contract | View source | |
| U10HD021373 | U.S. NIH Grant/Contract | View source | |
| U10HD021385 | U.S. NIH Grant/Contract | View source | |
| U10HD021397 | U.S. NIH Grant/Contract | View source | |
| U10HD027851 | U.S. NIH Grant/Contract | View source | |
| U10HD027853 | U.S. NIH Grant/Contract | View source | |
| U10HD027856 | U.S. NIH Grant/Contract | View source | |
| U10HD027871 | U.S. NIH Grant/Contract | View source | |
| U10HD027880 | U.S. NIH Grant/Contract | View source | |
| U10HD027904 | U.S. NIH Grant/Contract | View source | |
| U10HD034216 | U.S. NIH Grant/Contract | View source | |
| U10HD040461 | U.S. NIH Grant/Contract | View source | |
| U10HD040492 | U.S. NIH Grant/Contract | View source | |
| U10HD040498 | U.S. NIH Grant/Contract | View source | |
| U10HD040521 | U.S. NIH Grant/Contract | View source | |
| U10HD040689 | U.S. NIH Grant/Contract | View source | |
| M01RR000030 | U.S. NIH Grant/Contract | View source | |
| M01RR000039 | U.S. NIH Grant/Contract | View source | |
| M01RR000044 | U.S. NIH Grant/Contract | View source | |
| M01RR000070 | U.S. NIH Grant/Contract | View source | |
| M01RR000080 | U.S. NIH Grant/Contract | View source | |
| M01RR000633 | U.S. NIH Grant/Contract | View source | |
| M01RR000750 | U.S. NIH Grant/Contract | View source | |
| M01RR006022 | U.S. NIH Grant/Contract | View source | |
| M01RR007122 | U.S. NIH Grant/Contract | View source | |
| M01RR008084 | U.S. NIH Grant/Contract | View source | |
| M01RR016587 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Center for Research Resources (NCRR) | NIH |
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This large multicenter trial tested whether cerebral cooling initiated within 6 hours of birth and continued for 72 hours would reduce the risk of death and moderate to severe neurodevelopmental injury at 18-22 months corrected age. Infants at least 36 weeks gestation with an abnormal blood gas within 1 hour of birth, or a history of an acute perinatal event and a 10-min Apgar score <5, or continued need for ventilation were screened. Following a neurological exam, those with moderate to severe encephalopathy were randomized to a 72-hour period of total body cooling (cooling blanket, followed by slow re-warming). The study was conducted in two phases: Phase I (20 infants) were examined for the safety of an esophageal temperature of 34-35 C; Phase II (main trial, 200 infants) were evaluated for the safety and efficacy of an esophageal temperature of 33-34 C. Cardio-respiratory, electroencephalograms (EEGs), renal, metabolic, and hematologic status, and esophageal and abdominal skin temperature were monitored during the 72 hours of intervention. Surviving children were given neurodevelopmental examinations at 18-22 months corrected age and again at school age (6-7 years of age).
Perinatal cerebral hypoxia-ischemia injury is an important cause of death and neurodevelopmental disability. Data from animal models suggest that brain cooling immediately after injury is neuroprotective. Experience with total body cooling during surgery, accidental near drownings, and one Phase I trial of term infants suggest that it is effective and safe in children.
This large multicenter trial tested whether cerebral cooling initiated within 6 hours of birth and continued for 72 hours would reduce the risk of death and moderate to severe neurodevelopmental injury at 18-22 months corrected age. Infants at least 36 weeks gestation with an abnormal blood gas within 1 hour of birth, or a history of an acute perinatal event and a 10-min Apgar score <5, or continued need for ventilation were screened. Following a neurological exam, those with moderate to severe encephalopathy were randomized to a 72-hour period of total body cooling (cooling blanket, followed by slow re-warming). The study was conducted in two phases: Phase I (20 infants) were examined for the safety of an esophageal temperature of 34-35 C; Phase II (main trial, 200 infants) were evaluated for the safety and efficacy of an esophageal temperature of 33-34 C. Cardio-respiratory, electroencephalograms (EEGs), renal, metabolic, and hematologic status, and esophageal and abdominal skin temperature were monitored during the 72 hours of intervention.
Neurodevelopmental outcome was assessed at 18-22 mos of age by masked certified examiners. The outcome at 18-22 months showed that whole-body cooling reduces the risk of death or moderate to severe disability in infants with hypoxic ischemic encephalopathy.
Surviving infants were assessed at 6-7 years (school age).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Hypothermia | Experimental | Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours |
|
| Normothermic | Placebo Comparator | Placebo: Normothermic control group (with esophageal temperature at or near 37.0°C) for 96 hours |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Induced hypothermia | Device | Whole-body cooling using the Blanketrol II or III Units in the Automatic Control Mode with a YSI 400 series temperature probe placed in the distal esophagus over a 96-hour period |
| Measure | Description | Time Frame |
|---|---|---|
| Death or moderate or severe disability | 18-22 months corrected age |
| Measure | Description | Time Frame |
|---|---|---|
| Length of hospital stay | Until discharge | |
| Frequency of multi-organ dysfunction | Until discharge | |
| Withdrawal of support |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Seetha Shankaran, MD | Wayne State University | Principal Investigator |
| Abbot R. Laptook, MD | Brown University, Womens and Infants Hospital of Rhode Island | Principal Investigator |
| Michele C. Walsh, MD MS | Case Western Reserve University | Principal Investigator |
| Ronald N. Goldberg, MD | Duke University | Principal Investigator |
| Barbara J. Stoll, MD | Emory University | Principal Investigator |
| Brenda B. Poindexter, MD MS | Indiana University | Principal Investigator |
| Abhik Das, PhD | RTI International | Principal Investigator |
| Krisa P. Van Meurs, MD | Stanford University | Study Director |
| Waldemar A. Carlo, MD | University of Alabama at Birmingham | Principal Investigator |
| Neil N. Finer, MD |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Alabama at Birmingham | Birmingham | Alabama | 35233 | United States | ||
| Stanford University |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 14510323 | Background | Shankaran S, Laptook A. Challenge of conducting trials of neuroprotection in the asphyxiated term infant. Semin Perinatol. 2003 Aug;27(4):320-32. doi: 10.1016/s0146-0005(03)00047-8. | |
| 19281415 | Background | Shankaran S. Neonatal encephalopathy: treatment with hypothermia. J Neurotrauma. 2009 Mar;26(3):437-43. doi: 10.1089/neu.2008.0678. |
| Label | URL |
|---|---|
| NICHD Neonatal Research Network | View source |
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| Control | Device | Control group: standard care |
|
| Until discharge |
| Post-neonatal deaths | 18-22 months corrected age |
| Multiple disability | 18-22 months corrected age |
| Seizure disorders | 18-22 months corrected age |
| Rehospitalizations | 18-22 months corrected age |
| University of California, San Diego |
| Principal Investigator |
| Kurt Schibler, MD | Children's Hospital Medical Center, Cincinnati | Principal Investigator |
| Shahnaz Duara, MD | University of Miami | Principal Investigator |
| Dale L. Phelps, MD | University of Rochester | Principal Investigator |
| Pablo J. Sanchez, MD | University of Texas, Southwestern Medical Center at Dallas | Principal Investigator |
| Kathleen A. Kennedy, MD MPH | The University of Texas Health Science Center, Houston | Principal Investigator |
| T. Michael O'Shea, MD | Wake Forest University | Principal Investigator |
| Richard A. Ehrenkranz, MD | Yale University | Principal Investigator |
| Palo Alto |
| California |
| 94304 |
| United States |
| Yale University | New Haven | Connecticut | 06504 | United States |
| University of Miami | Miami | Florida | 33136 | United States |
| Emory University | Atlanta | Georgia | 30303 | United States |
| Indiana University | Indianapolis | Indiana | 46202 | United States |
| Harvard University | Cambridge | Massachusetts | 02138 | United States |
| Wayne State University | Detroit | Michigan | 48201 | United States |
| University of New Mexico | Albuquerque | New Mexico | 87131 | United States |
| RTI International | Durham | North Carolina | 27705 | United States |
| Cincinnati Children's Medical Center | Cincinnati | Ohio | 45267 | United States |
| Case Western Reserve University, Rainbow Babies and Children's Hospital | Cleveland | Ohio | 44106 | United States |
| Brown University, Women & Infants Hospital of Rhode Island | Providence | Rhode Island | 02905 | United States |
| University of Tennessee | Memphis | Tennessee | 38163 | United States |
| University of Texas Southwestern Medical Center at Dallas | Dallas | Texas | 75235 | United States |
| University of Texas Health Science Center at Houston | Houston | Texas | 77030 | United States |
| 19762176 | Background | Higgins RD, Shankaran S. Hypothermia for hypoxic ischemic encephalopathy in infants > or =36 weeks. Early Hum Dev. 2009 Oct;85(10 Suppl):S49-52. doi: 10.1016/j.earlhumdev.2009.08.015. Epub 2009 Sep 17. |
| 16221780 | Result | Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, Fanaroff AA, Poole WK, Wright LL, Higgins RD, Finer NN, Carlo WA, Duara S, Oh W, Cotten CM, Stevenson DK, Stoll BJ, Lemons JA, Guillet R, Jobe AH; National Institute of Child Health and Human Development Neonatal Research Network. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005 Oct 13;353(15):1574-84. doi: 10.1056/NEJMcps050929. |
| 12165594 | Result | Shankaran S, Laptook A, Wright LL, Ehrenkranz RA, Donovan EF, Fanaroff AA, Stark AR, Tyson JE, Poole K, Carlo WA, Lemons JA, Oh W, Stoll BJ, Papile LA, Bauer CR, Stevenson DK, Korones SB, McDonald S. Whole-body hypothermia for neonatal encephalopathy: animal observations as a basis for a randomized, controlled pilot study in term infants. Pediatrics. 2002 Aug;110(2 Pt 1):377-85. doi: 10.1542/peds.110.2.377. |
| 17079582 | Result | Ambalavanan N, Carlo WA, Shankaran S, Bann CM, Emrich SL, Higgins RD, Tyson JE, O'Shea TM, Laptook AR, Ehrenkranz RA, Donovan EF, Walsh MC, Goldberg RN, Das A; National Institute of Child Health and Human Development Neonatal Research Network. Predicting outcomes of neonates diagnosed with hypoxemic-ischemic encephalopathy. Pediatrics. 2006 Nov;118(5):2084-93. doi: 10.1542/peds.2006-1591. |
| 18534246 | Result | Oh W, Perritt R, Shankaran S, Merritts M, Donovan EF, Ehrenkranz RA, O'Shea TM, Tyson JE, Laptook AR, Das A, Higgins RD. Association between urinary lactate to creatinine ratio and neurodevelopmental outcome in term infants with hypoxic-ischemic encephalopathy. J Pediatr. 2008 Sep;153(3):375-8. doi: 10.1016/j.jpeds.2008.03.041. Epub 2008 May 9. |
| 18720323 | Result | Mietzsch U, Parikh NA, Williams AL, Shankaran S, Lasky RE. Effects of hypoxic-ischemic encephalopathy and whole-body hypothermia on neonatal auditory function: a pilot study. Am J Perinatol. 2008 Aug;25(7):435-41. doi: 10.1055/s-0028-1083842. Epub 2008 Aug 21. |
| 18762517 | Result | Laptook A, Tyson J, Shankaran S, McDonald S, Ehrenkranz R, Fanaroff A, Donovan E, Goldberg R, O'Shea TM, Higgins RD, Poole WK; National Institute of Child Health and Human Development Neonatal Research Network. Elevated temperature after hypoxic-ischemic encephalopathy: risk factor for adverse outcomes. Pediatrics. 2008 Sep;122(3):491-9. doi: 10.1542/peds.2007-1673. |
| 18829776 | Result | Shankaran S, Pappas A, Laptook AR, McDonald SA, Ehrenkranz RA, Tyson JE, Walsh M, Goldberg RN, Higgins RD, Das A; NICHD Neonatal Research Network. Outcomes of safety and effectiveness in a multicenter randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy. Pediatrics. 2008 Oct;122(4):e791-8. doi: 10.1542/peds.2008-0456. |
| 19020525 | Result | Parikh NA, Lasky RE, Garza CN, Bonfante-Mejia E, Shankaran S, Tyson JE. Volumetric and anatomical MRI for hypoxic-ischemic encephalopathy: relationship to hypothermia therapy and neurosensory impairments. J Perinatol. 2009 Feb;29(2):143-9. doi: 10.1038/jp.2008.184. Epub 2008 Nov 20. |
| 19252411 | Result | Lasky RE, Parikh NA, Williams AL, Padhye NS, Shankaran S. Changes in the PQRST intervals and heart rate variability associated with rewarming in two newborns undergoing hypothermia therapy. Neonatology. 2009;96(2):93-5. doi: 10.1159/000205385. Epub 2009 Mar 2. |
| 19948631 | Result | Laptook AR, Shankaran S, Ambalavanan N, Carlo WA, McDonald SA, Higgins RD, Das A; Hypothermia Subcommittee of the NICHD Neonatal Research Network. Outcome of term infants using apgar scores at 10 minutes following hypoxic-ischemic encephalopathy. Pediatrics. 2009 Dec;124(6):1619-26. doi: 10.1542/peds.2009-0934. |
| 20921569 | Result | Kwon JM, Guillet R, Shankaran S, Laptook AR, McDonald SA, Ehrenkranz RA, Tyson JE, O'Shea TM, Goldberg RN, Donovan EF, Fanaroff AA, Poole WK, Higgins RD, Walsh MC; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Clinical seizures in neonatal hypoxic-ischemic encephalopathy have no independent impact on neurodevelopmental outcome: secondary analyses of data from the neonatal research network hypothermia trial. J Child Neurol. 2011 Mar;26(3):322-8. doi: 10.1177/0883073810380915. Epub 2010 Oct 4. |
| 3124102 | Result | MacKay VL, Welch SK, Insley MY, Manney TR, Holly J, Saari GC, Parker ML. The Saccharomyces cerevisiae BAR1 gene encodes an exported protein with homology to pepsin. Proc Natl Acad Sci U S A. 1988 Jan;85(1):55-9. doi: 10.1073/pnas.85.1.55. |
| 35835616 | Derived | Bonifacio SL, Chalak LF, Van Meurs KP, Laptook AR, Shankaran S. Neuroprotection for hypoxic-ischemic encephalopathy: Contributions from the neonatal research network. Semin Perinatol. 2022 Nov;46(7):151639. doi: 10.1016/j.semperi.2022.151639. Epub 2022 Jun 10. |
| 33038899 | Derived | Pappas A, Shankaran S, McDonald SA, Carlo WA, Laptook AR, Tyson JE, Das A, Skogstrand K, Hougaard DM, Higgins RD. Blood Biomarkers and 6- to 7-Year Childhood Outcomes Following Neonatal Encephalopathy. Am J Perinatol. 2022 May;39(7):732-749. doi: 10.1055/s-0040-1717072. Epub 2020 Oct 10. |
| 27776752 | Derived | Shankaran S, Laptook AR, McDonald SA, Hintz SR, Barnes PD, Das A, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health, and Human Development Neonatal Research Network. Acute Perinatal Sentinel Events, Neonatal Brain Injury Pattern, and Outcome of Infants Undergoing a Trial of Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy. J Pediatr. 2017 Jan;180:275-278.e2. doi: 10.1016/j.jpeds.2016.09.026. Epub 2016 Oct 21. |
| 26387012 | Derived | Shankaran S, McDonald SA, Laptook AR, Hintz SR, Barnes PD, Das A, Pappas A, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Neonatal Magnetic Resonance Imaging Pattern of Brain Injury as a Biomarker of Childhood Outcomes following a Trial of Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy. J Pediatr. 2015 Nov;167(5):987-93.e3. doi: 10.1016/j.jpeds.2015.08.013. Epub 2015 Sep 16. |
| 24019415 | Derived | Vohr BR, Stephens BE, McDonald SA, Ehrenkranz RA, Laptook AR, Pappas A, Hintz SR, Shankaran S, Higgins RD, Das A; Extended Hypothermia Follow-up Subcommittee of the NICHD Neonatal Research Network. Cerebral palsy and growth failure at 6 to 7 years. Pediatrics. 2013 Oct;132(4):e905-14. doi: 10.1542/peds.2012-3915. Epub 2013 Sep 9. |
| 22646631 | Derived | Shankaran S, Pappas A, McDonald SA, Vohr BR, Hintz SR, Yolton K, Gustafson KE, Leach TM, Green C, Bara R, Petrie Huitema CM, Ehrenkranz RA, Tyson JE, Das A, Hammond J, Peralta-Carcelen M, Evans PW, Heyne RJ, Wilson-Costello DE, Vaucher YE, Bauer CR, Dusick AM, Adams-Chapman I, Goldstein RF, Guillet R, Papile LA, Higgins RD; Eunice Kennedy Shriver NICHD Neonatal Research Network. Childhood outcomes after hypothermia for neonatal encephalopathy. N Engl J Med. 2012 May 31;366(22):2085-92. doi: 10.1056/NEJMoa1112066. |
| ID | Term |
|---|---|
| D020925 | Hypoxia-Ischemia, Brain |
| D007035 | Hypothermia |
| ID | Term |
|---|---|
| D002545 | Brain Ischemia |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D002534 | Hypoxia, Brain |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D000860 | Hypoxia |
| D012818 | Signs and Symptoms, Respiratory |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D001832 | Body Temperature Changes |
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| ID | Term |
|---|---|
| D007036 | Hypothermia, Induced |
| ID | Term |
|---|---|
| D017679 | Cryotherapy |
| D013812 | Therapeutics |
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